tbuckley/cabot-search huggingface dataset:
Abstract B003: Causal effect of type II diabetes on prostate cancer in the East Asian population: A two-sample Mendelian randomization study
Authors: Zhongyi Guo
Journal: Cancer Research (2023)

Abstract Type II diabetes, a metabolic disease, and prostate cancer are prevalent diseases in the elderly population. Whether type II diabetes has an association with prostate cancer has not been thoroughly studied. Limited research has been performed from a perspective of genetic level, especially among non-European populations. In this study, we used a two-sample Mendelian randomization (MR) approach to evaluate the causal effect between type II diabetes as an exposure and prostate cancer as an outcome in the East Asian population. For type II diabetes, we used 174 risk loci identified in a meta-analysis of 77,418 cases and 356,122 controls from 23 East Asian Genome-wide Association Studies (GWAS). For prostate cancer, summary statistics were extracted from the GWAS from BioBank Japan using 5,408 cases and 103,939 controls. We performed two-sample Mendelian randomization with the inverse variance weighted method while using MR Egger and weighted median methods as sensitivity analysis. For type II diabetes risk SNPs not directly present in the prostate cancer GWAS, we identified proxy SNPs in linkage disequilibrium (LD, r2 &amp;gt; 0.8) using the 1000 genome project. We used P-value &amp;lt; 0.05 as a threshold to determine statistical significance. Based on 152 out of 174 SNPs of type II diabetes in the East Asian population, we found that type II diabetes had a significant negative causal effect on prostate cancer [Odds Ratio (OR) = 0.76, 95% Confidence Interval (CI): 0.76 - 0.89, P = 2.26 x 10-6]. Results from sensitivity analysis using other weighting methods provided similar results. In conclusion, we observed an inverse relationship between type II diabetes and prostate cancer among the East Asian population. Patients with diabetes may have a lower risk of prostate cancer due to a reduced level of insulin and testosterone. To validate this association, further research is needed on those hormones and prostate cancer risk at the metabolic level. Citation Format: Zhongyi Guo. Causal effect of type II diabetes on prostate cancer in the East Asian population: A two-sample Mendelian randomization study [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B003.
Abstract B015: Racial differences in epigenetic aging and its impact on expression of T-cell inhibitory receptors
Authors: Ping-Ching Hsu, Michael Bauer, Tung-Chin Chiang, Lora J. Rogers, A. Murat Aydin, L. Joseph Su, Brian Koss
Journal: Cancer Research (2023)

Abstract Introduction: Accelerated aging is associated with lifetime stress and frailty, and has been reported in aging-related disease and mortality, including lung cancer, postmenopausal breast cancer, childhood cancer, and coronary heart disease. However, current knowledge on the impact of epigenetic aging in anti-tumor immunity remains limited. Pre-existing immune status heavily contributes to cancer diagnosis and the success of immunotherapy treatment, therefore, the relationship between epigenetic aging and immune function, and how it may lead to racial health disparity needs to be further explored. Methods: Genome-wide DNA methylation analysis were conducted in a feasibility test of 16 participants with equal number of African Americans (AAs) and European Americans (EAs), and epigenetic age (mAge) were calculated using R package methylclock for the established multi-tissue epigenetic clock algorithms which consists of 353 CpGs by Horvath. Correlation analysis was performed between mAge and in vitro T cell activation tests. Results: As expected, high correlation of calculated mAge versus chronological age was observed from 16 participants using the Horvath calculator, with higher mAge in AAs than EAs. Significant separation in DNA methylation profiles between AAs and EAs existed based on the top 1,000 CpG sites from the principal component analysis. To understand the effects of aging on T cell function, a series of functional assays were performed from different age groups, and significant (P&amp;lt;0.05) negative correlations of Age and mAge to flow cytometry defined naïve lymphocyte subsets were detected. Significant positive correlations between mAge and the expression of T-cell inhibitory receptors CTLA4 and TIGIT were observed in activated T cells from this sample population. Conclusion: The human immune system undergoes dramatic aging-related changes, which continuously progress and contribute to the decline in immune-mediated protection against infections and cancer. Our study serves as a proof-of-principle to highlight the degree of accelerated epigenetic aging and its impact on T cells function among different racial and age groups), which warrants further research that may shed more light into therapeutic cellular immune responses and mechanisms of immune-related adverse events in patients treated with immunotherapy for cancer. Citation Format: Ping-Ching Hsu, Michael Bauer, Tung-Chin Chiang, Lora J. Rogers, A. Murat Aydin, L. Joseph Su, Brian Koss. Racial differences in epigenetic aging and its impact on expression of T-cell inhibitory receptors [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B015.
Vitiligo evidence-based expert consensus recommendations for paediatric and adolescent patients: part I—topical therapeutics
Authors: Yael Renert-Yuval, Khaled Ezzedine, Pearl Grimes, David Rosmarin, Lawrence Eichenfield, Leslie Castelo-Soccio, Victor Huang, Seemal R Desai, Samantha Walsh, Jonathan I Silverberg, Amy S Paller, Mark Weingarten, Shanthi Narla, Jackie Gardner, Michael Siegel, Nanette B Silverberg
Journal: British Journal of Dermatology (2023)

Abstract No United States paradigm for the treatment of paediatric, adolescent and young adult vitiligo has been developed. To develop evidence and consensus-based expert opinion to promote therapeutic consistency for the diagnosis and treatment of vitiligo. An IRB-exempted process was developed to produce consensus recommendations based on literature review and SORT criteria. Research questions were reviewed on 9 May 2022 in a video-based conference. Forty-two recommendations were made on the diagnosis of vitiligo (5) and optimal topical therapeutics (37). Topical calcineurin inhibitors, topical corticosteroids and topical ruxolitinib 1·5% cream were all identified as potential first-line therapies in the management of paediatric and adolescent patients with specific guidance on age-based data, frequency of application, minimum length of the therapeutic trial and coordinated usage of ultraviolet light therapy. The literature on paediatric and adolescent vitiligo has a heterogeneous methodology and lack of patient-reported outcomes. Children with vitiligo may be effectively managed with a variety of topical agents as first- and second-line therapy. Evidence supports the utility of topical calcineurin inhibitors, topical corticosteroids and topical JAK inhibitors, with limitations based on factors such as location, body surface area and age.
Vitiligo is associated with mental health disorders, substance abuse, cardiovascular risk factors and events, and venous thromboembolism: analysis of the 2015–2019 nationwide emergency department sample
Authors: Jorge A Rios-Duarte, Jonathan I Silverberg
Journal: British Journal of Dermatology (2023)

Abstract Vitiligo is a chronic inflammatory depigmenting skin disease that is associated with psychosocial burden and quality of life impact. Previous studies show that patients with vitiligo have an increased likelihood of autoimmune diseases, but they reveal conflicting results regarding mental health disorders, cardiovascular disease, venous thromboembolism and other comorbidities. We sought to investigate the association of vitiligo with a variety of comorbid health disorders. Data were analysed from 2015 to 2019 Nationwide Emergency Department Sample (NEDS), including a representative 20% sample of all emergency department visits in the United States. Vitiligo and comorbidities were identified by using the international classification of disease 10 codes. Associations of vitiligo with various comorbidities were tested using weighted multivariable logistic regression models. The most frequent comorbidities diagnosed in patients presenting to the emergency department with vitiligo were essential hypertension [weighted prevalence (95% confidence interval, CI): 37·0% (34·6–39·0%)], followed by hyperlipidaemia [30·0% (27·7–32·0%)], hypothyroidism [22·9% (20·7–25·0%)], gastro-esophageal reflux disease without esophagitis [19·2% (17·6–21·0%)], history of nicotine dependence [18·1% (16·5–20·0%)], acute kidney failure [16·1% (14·7–18·0%)], atherosclerotic heart disease without angina [14·8% (13·2–17·0%)] and type 2 diabetes mellitus without complications [14·0% (12·1–16·0%)]. In multivariable logistic regression models adjusting for sex, age and insurance status, vitiligo was associated with alcohol use disorder [adjusted odds ratio (95% CI): 1·88 (1·68–2·11)], anxiety spectrum disorders [1·80 (1·65–1·96)], asthma [1·82 (1·65–2·01)], atrial fibrillation [1·49 (1·35–1·65)], coronary artery disease [1·79 (1·63–1·96)], depressive disorders [2·18 (2·00–2·38)], diabetes mellitus [2·65 (2·42–2·91)], myocardial infarction [2·32 (1·98–2·72)], heart failure [2·09 (1·91–2·28)], hyperlipidaemia [2·66 (2·45–2·88)], hypertension [2·16 (1·96–2·39)], hyperthyroidism [12·59 (11·07–14·32)], hypothyroidism [5·46 (4·95–6·02)], peripheral artery disease [2·69 (2·05–3·53)], pneumonia [2·20 (2·00–2·43)], sleep apnoea [2·43 (2·16–2·74)], stroke [1·81 (1·57–2·08)], suicide ideation or attempt [1·67 (1·39–2·01)] and venous thrombosis and pulmonary embolism [2·46 (2·12–2·85)]. These results show that patients with vitiligo have a significantly higher likelihood of comorbid mental health disorders, substance abuse, cardiovascular risk factors and events, and venous thromboembolism.
Ritlecitinib (PF-06651600), an oral JAK3/TEC inhibitor, shows efficacy in patients with active nonsegmental vitiligo and either a lighter or darker Fitzpatrick skin type: results from a phase 2b, randomized, dose-ranging study with an extension period
Authors: Elena Peeva, Yuji Yamaguchi, Brett King, George Han, Lori Ann Cox, Anindita Banerjee, Mauro Picardo, Jung Min Bae, Abigail Sloan, Rodney Sinclair, Khaled Ezzedine
Journal: British Journal of Dermatology (2023)

Abstract Ritlecitinib, an oral JAK3/TEC inhibitor, inhibits cytokines IL-15 and IFN-γ that play a critical role in vitiligo pathogenesis. In a phase 2b trial, ritlecitinib demonstrated a significant improvement on the centrally read Facial Vitiligo Area Scoring Index (crF-VASI) at Week 24 in patients with active nonsegmental vitiligo (NSV) at 50 mg daily with or without a loading dose (100 or 200 mg daily for 4 weeks). Improvement on the crF-VASI was observed up to Week 48 in patients receiving ritlecitinib 50 mg daily with a 200 mg daily loading dose for 4 weeks in the 24-week extension period. We evaluated the efficacy and safety of ritlecitinib, an oral JAK3/TEC inhibitor, in patients with active NSV and lighter Fitzpatrick skin types (FST; I–III) or darker FST (IV–VI) from the Phase 2b study (NCT03715829). Patients with active NSV were randomized to placebo or ritlecitinib 50 mg daily with or without a loading dose (200 or 100 mg, 4-week) or low doses (30 or 10 mg) in a 24-week, dose-ranging period, followed by a 24-week extension wherein patients were allocated to 200/50 mg (200 mg, 4-week; 50 mg, 20-week). Percent change from baseline (%CFB) in F-VASI was evaluated. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs). A total of 253 patients (lighter FST, n = 170; darker FST, n = 83) completed the dose-ranging period. Placebo-adjusted mean %CFB in F-VASI at Week 24 among the 50 mg and low-dose groups, respectively, were −15·2 (P = 0·0043) and −5·5 (P = 0·1991) in lighter FST and −37·4 (P &amp;lt; 0·0001) and −15·7 (P = 0·0401) in darker FST. In the extension, 187 patients received 200/50 mg and 136 (lighter FST, n = 96; darker FST, n = 40) completed Week 48. Continuous re-pigmentation without plateau of effect was observed across FST through Week 48; mean %CFB in F-VASI at Week 48 in patients initially treated with 50 mg, low doses or placebo in the dose-ranging period, respectively, were −63·1, −51·0 and −51·3 for lighter FST and −66·8, −51·0 and −52·5 for darker FST. TEAE incidence in the dose-ranging period was similar between lighter and darker FST (range, 69·2–81·0%). Ritlecitinib was generally safe with similar efficacy in vitiligo patients with lighter or darker FST.
Abstract PR010: Aging-induced reprogramming of the cell of origin defines lung cancer evolution
Authors: Xueqian Zhuang, Simon Joost, Qing Wang, Melissa Blum, Selena Ding, Zhuxuan Li, Yingqian Zhan, Richard Koche, Emily Wong, Tuomas Tammela
Journal: Cancer Research (2023)

Abstract Aging is one of the most important risk factors for cancer development. However, our understanding of how aging impacts cancer evolution remains at an early stage. We investigated the evolution of lung adenocarcinoma (LUAD) in aged vs. young KrasLSL-G12D/+; Trp53flox/flox (KP) mice. Surprisingly, we found that LUAD initiation and progression were significantly impaired with aging. Using functional in vivo and in vitro assays, we demonstrated that the loss of tumor-initiating potential could be attributed to a loss of stemness in the alveolar type 2 (AT2) cells, which are the predominant cell of origin for LUAD. We next explored the biology of the tumors that formed in aged KP mice using single-cell transcriptomics. We discovered a distinct compositional landscape of cancer cell subsets in aged lung tumors, revealing a delay in the molecular progression of the cancers and an aging-specific gene expression signature. Interestingly, key components of this gene signature could be traced back to specific epigenetic alterations in the AT2 cells. Furthermore, the aged mouse LUAD signature was highly predictive of patient age in human LUAD, indicating conservation of the age-associated changes across species. We hypothesized that the aging-associated changes in gene expression during LUAD tumorigenesis may underpin delayed tumor progression in the aged KP mice. To test this, we performed an in vivo genetic screen in the autochthonous KP model and identified genetic dependencies that were specific to LUAD in aged or young mice. Our results indicate that aging-associated epigenetic changes in the cell of origin are imprinted on evolving tumors, which determines tumor initiation potential, alters trajectory of tumor evolution, and leads to age-dependent vulnerabilities. These findings suggest that the biology of tumors is fundamentally altered by aging, raising new possibilities for cancer treatment and prevention in patients of different ages. Citation Format: Xueqian Zhuang, Simon Joost, Qing Wang, Melissa Blum, Selena Ding, Zhuxuan Li, Yingqian Zhan, Richard Koche, Emily Wong, Tuomas Tammela. Aging-induced reprogramming of the cell of origin defines lung cancer evolution [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR010.
Abstract B019: Aging-induced reprogramming of the cell of origin defines lung cancer evolution
Authors: Xueqian Zhuang, Simon Joost, Qing Wang, Melissa Blum, Selena Ding, Zhuxuan Li, Yingqian Zhan, Richard Koche, Emily Wong, Tuomas Tammela
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR010) of the Conference Proceedings. Citation Format: Xueqian Zhuang, Simon Joost, Qing Wang, Melissa Blum, Selena Ding, Zhuxuan Li, Yingqian Zhan, Richard Koche, Emily Wong, Tuomas Tammela. Aging-induced reprogramming of the cell of origin defines lung cancer evolution [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B019.
Abstract IA001: DNA damage repair: Impact on aging and cancer and applications of nutritional interventions
Authors: Jan H Hoeijmakers
Journal: Cancer Research (2023)

Abstract Rare DNA repair syndromes display strong cancer predisposition and/or premature aging, indicating that DNA damage underlies both, consistent with the notion that age is the most important risk factor for cancer. We have generated a series of DNA-repair-deficient mouse mutants, and discovered that defects in transcription-coupled repair cause accelerated, segmental aging and overprotect from cancer, whereas global genome repair defects are predominantly associated with cancer. When combined aging is dramatically accelerated, indicating a dose-dependent causal relationship. We also found that premature aging triggers a potent anti-aging ‘survival response’, which suppresses growth (IGF1) and enhances resilience and defenses, resembling the longevity response induced by dietary restriction (DR). Interestingly, subjecting progeroid mutants to actual DR tripled lifespan, and drastically retarded accelerated aging, most notably neurodegeneration. We also found that DR lowered DNA damage, explaining how DR counteracts aging and cancer and why DNA repair mutants overrespond to DR. Interestingly, expression profiles of progeroid mutants showed gradual decline of expression in a genelength-dependent manner, due to genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. This transcription stress is also prominent in normal aging of many (post-mitotic) tissues and explains protein aggregation in dementias. DR largely alleviated transcription stress and hence prolongs genome function. I will present phenotypes of conditional DNA repair models targeting aging to selected organs, striking parallels with Alzheimer’s disease and the first remarkable results translating these concepts from mice to repair-deficient children. Our findings identify DNA damage as main cause of aging, establish repair-deficient mice as models for interventions to promote healthy aging, explain the molecular anti-aging, anti-cancer mechanism of DR and the aging component of proteinopathies based on transcription stress and promote counterintuitive DR-like interventions for progeroid syndromes, for preventing neurodegenerative diseases and ischemia reperfusion damage in surgery and for improving chemotherapy outcome and reducing side effects. Citation Format: Jan H Hoeijmakers. DNA damage repair: Impact on aging and cancer and applications of nutritional interventions [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA001.
Abstract A014: Cytokines surge in the blood years prior to a cancer diagnosis in elderly individuals
Authors: Guangbo Chen, Hong Zheng, Yael Rosenberg-Hasson, Saron Araya, Cindy Padilla, Kavita Sarin, Cornelia L. Dekker, Philip Grant, Holden T. Maecker, David Furman, Shai Shen-Orr, Purvesh Khatri, Mark M. Davis
Journal: Cancer Research (2023)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR002) of the Conference Proceedings. Citation Format: Guangbo Chen, Hong Zheng, Yael Rosenberg-Hasson, Saron Araya, Cindy Padilla, Kavita Sarin, Cornelia L. Dekker, Philip Grant, Holden T. Maecker, David Furman, Shai Shen-Orr, Purvesh Khatri, Mark M. Davis. Cytokines surge in the blood years prior to a cancer diagnosis in elderly individuals [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A014.
Abstract PR013: BH3 profiling of senescent cancer cells to identify mechanisms of resistance to ABT-263
Authors: Fleur Jochems, Julie A. MacDonald, Chrysiida Baltira, Veerle Daniels, Mark de Gooijer, Olaf Van Tellingen, Anthony Letai, René Bernards
Journal: Cancer Research (2023)

Abstract Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents. ABT-263 is a broad acting senolytic that targets anti-apoptotic proteins BCL-2, BCL-xL and BCL-W. Our group has shown that ABT-263 has a senolytic effect in most cancer cell lines, but not in all. This raised the question why certain senescent cancer cells undergo into apoptosis after treatment with ABT-263, while others remain refractory. To investigate this, we performed BH3 profiling, a technique that measures apoptotic priming (readiness to undergo into apoptosis) and apoptotic dependencies. We found that BH3 profiling in senescent cells requires specific optimization, and it determines that senescent ABT-263 sensitive cells highly depend on specific anti-apoptotic signaling, while ABT-263 resistant cells did not. Moreover, we found that ABT-263 sensitive cells were more primed to apoptosis compared to resistant cells. Intriguingly, this correlation was already apparent in the parental state. Nevertheless, we found that senescent cells were less primed to apoptosis than their parental counterparts, which was in contrast to what we expected. In conclusion, whether senescent cells will respond to ABT-263 is already determined in the parental state, and they become dependent on anti-apoptotic signaling for their survival. The observation that senescent cells were less primed to apoptosis was surprising, and we intend to further understand how it is possible that senescent cells are less primed to apoptosis, but still sensitive to ABT-263. Citation Format: Fleur Jochems, Julie A. MacDonald, Chrysiida Baltira, Veerle Daniels, Mark de Gooijer, Olaf Van Tellingen, Anthony Letai, René Bernards. BH3 profiling of senescent cancer cells to identify mechanisms of resistance to ABT-263 [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR013.